Method of treatment

ABSTRACT

Compounds of the formula 1   AND THE PHARMACOLOGICALLY ACCEPTABLE ACID ADDITION SALTS THEREOF, WHEREIN R1 is hydrogen, lower-alkyl, lower alkoxy, halogen or -CF3; R2 is hydrogen, lower-alkyl, lower-alkoxy, halogen or -CF3 and R3 is lower alkyl are prepared in pharmacologically acceptable formulations are used treating hypertension in warm-blooded, hypertensive animals free of helminthic infestations by administration of such compounds and compositions thereof at a dosage of from 5-50 mg./kg. per day.

United States Patent n 1 Skaletzky METHOD OF TREATMENT [75] Inventor: Louis L. SkaIetzky, Kalamazoo,

Mich.

[73] Assignee: The Upjohn Company, Kalamazoo,

Mich.

[221 Filed: Jan. 24, 1972 [211 Appl. No.: 220,406

Related US. Application Data 1 [63] Continuation-impart of Ser. No. 44,903, June 9, I970,

Primary Examiner-Jerome D. Goldberg Att0rney-Hans L. Berneis et al.

[111 3,760,081 1 Sept. 18, 1973 [57] ABSTRACT Compounds of the formula I and the pharmacologically acceptable acid addition salts thereof, wherein R is hydrogen, lower-alkyl, lower alkoxy, halogen or -CF R is hydrogen, loweralkyl, lower-alkoxy, halogen or -CF and R is lower alkyl are prepared in pharmacologically acceptable formulations are used treating hypertension in warmblooded, hypertensive animals free of helminthic infestations by administration of such compounds and compositions thereof at a dosage of from 550 mg./kg. per day.

4 Claims, No Drawings METHOD OF TREATMENT CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation-in-part application of application Ser. No. 44,903, filed June 9, 1970, and

now abandoned.

BACKGROUND OF THE INVENTION 1-. Field of the Invention This invention is concerned with a method of treatment for hypertension with new and old organic compounds. More particularly this invention relates to 2- alkanoamidobenzimidazoles of the formula I:

wherein R, is selected from the group consisting of hydrogen, alkyl of one to six carbon atoms, inclusive, alkoxy of one to six carbon atoms, inclusive, chlorine, bromine, fluorine, and CF;,; wherein R is selected from the group consisting of hydrogen, alkyl, defined as above, chlorine, bromine, fluorine, alkoxy defined as above, and CF and wherein R is alkyl of one to four carbon atoms, inclusive, and their use.

2. Description of the Prior Art The compounds of formula I above, the process of preparing them has been described in U.S. Pat. Nos. 3,336,191 and 3,401,171. In these patents the use of these compounds is anthelmintic. From 5 to 500 mg./kg. perday is administered to animals (U.S. Pat. No. 3,336,191). No disclosure of antihypertensive action has been noted in these patents.

BRIEF SUMMARY OF THE INVENTION This invention is concerned with new organic compounds, their use and the use of known compounds,

and more particularly with the use of 2- alkanoamidobenzimidazoles H O N N-a-R; 1 i6 2 R 5 a ---N \V H Also included is the use of these compounds as pharmacologically acceptable acid addition salts, and in formulations with other active hypertensive reagents, diuretics, tranquilizers or with pharmacological acceptable carriers. Another objective of this invention is the method of treatment for hypertension in warm-blooded animals by administration of the above compounds or formulations thereof.

DESCRIPTION OF THE PREFERRED EMBODIMENTS The alkyl groups of one to six and one to four carbon atoms, inclusive, in formula I are exemplified by methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec. butyl, pnetyl, Z-methylbutyl, hexyl, 2-methylpentyl, 3- methylbutyl, 2,2-dimethylbutyl, and the like.

The alkoxy groups of one to six carbon atoms include methoxy, ethoxy, propoxy, butoxy, isopropoxy, isobutyloxy, sec. butoxy, pentoxy, hexoxy, 2- methylpentoxy, S-methylpentoxy and the like.

The pharmacological acid addition salts include the hydrochlorides, hydrobromides, sulfates, phosphates, acetates, salicylates, cyclohexanesulfamates, methanesulfonates, ethanesulfonates tartrates, citrates, malonates, lactates, and the like.

The new compounds of formula 1 are made by the methods disclosed in U.S. Pat. Nos. 3,336,191 and 3,401.171, or equivalent British Patents, e.g., No. 1,122,957. The process of preparing the new products of this invention, 2-acetamido-5 ,6- dimethylbenzimidazole, and hydrochloride thereof is shown in Examples 1. These Examples are also illustra tive for the production of other compounds of formula 1, whose synthesis may not be specifically disclosed in the prior-disclosed patents.

A compound of the Formula I or pharrnacologically acceptable acid addition salts thereof are presented for oral administration in solid and liquid unit dosage forms, such as tablets, capsules, powders, granules, syrups, elixirs, and the like, containing suitable quantities of the compound.

Powders are quite simply prepared by comminuting a compound of the Formula 1 orpharmacologically acceptable acid addition salts thereof to a suitably fine size and mixing with a similarly comminuted diluent. The diluent can be an edible carbohydrate material such as starch or lactose. Advantageously, a sweetening agent or sugar is present as well as a flavoring agent. Dry granulations for reconstitution with water are prepared utilizing water-soluble diluents. A powder mixture of finely divided compound of the Formula I or pharmacologically acceptable acid addition salts thereof and a water-soluble diluent such as sucrose, glucose, and the like, is wetted with a binder such as acacia mucilage or geltain solution and forced through a screen to form granules which are allowed to dry. Advantageously, a thickening or suspending agent such as methylcellulose is present as well as a wetting and flavoring agent.

Capsules are produced by preparing a powder mixture as hereinbefore described and filling into formed geltain sheaths. Advantageously, as an adjuvant to the filling operation, a lubricant such as talc, magnesium stearate and calcium stearate is added to the powder mixture before the filling operation.

wetting with a binder such as corn syrup, gelatin solution, methylcellulose solution or acacia mucilage and forcing through a screen. An alternative granulating procedure is slugging the powder mixture, i.e., run the powder mixture through a tablet machine and breaking the resulting large tablets into pieces (slugs). The slugs can be lubricated to prevent sticking to the tabletforming dies by means of the addition of stearic acid, a stearate salt, talc, or mineral oil. The lubricated mixture is then compressed into tablets of the required weight.

Advantageously, the tablet can be provided with a protective coating consisting of a sealing coat of shellac, a coating of sugar and methylcellulose and a polish coating of camauba wax.

Oral fluids are prepared in unit dosage forms such as syrups and elixirs wherein each teaspoonful of composition contains a predetermined amount of a compound of the Formula 1 and pharmacologically acceptable acid addition salts thereof for administration.

A syrup is prepared using a water soluble salt of a compound of the Formula I in a suitable flavored aqueous sucrose solution. Similarly an elixir is prepared utilizing a hydroalcoholic vehicle. Elixirs are advantageous vehicles for use when another therapeutic agent which is not sufficiently water soluble is to be included in the composition.

For parenteral administration aqueous fluid unit dosage forms can be prepared. In preparing the parenteral form, a measured amount of a water soluble salt of a compound of the Formula I and a pharmcologically acceptable acid is placed in a vial, the vial and its contents sterilized and sealed. An accompanying vial of sterile water is provided as a vehicle to form a solution prior to administration. Advantageously, the sterile water can have dissolved therein a local anesthetic and buffering agents.

Alternately, a parenteral suspension can be prepared by suspending an insoluble form of a compound of the Formula I in a sterile aqueous vehicle or in a parenterally acceptable vegetable oil with or without additional adjuvants.

For the treatment of warm-blooded hypertensive animals free of helminthic infestation by oral administration, a compound of the Formula I and pharmacologically acceptable acid addition salts thereof is conveniently prepared in the form of a food premix. The food premix can comprise the active material in admixture with an edible diluent such as starch, oatmeal, flour, calcium carbonate, talc, dried fish meal and the like non-toxic, orally acceptable edible diluents. The prepared premix is then conveniently added to the regular feed, thereby providing medication to the animal in the course of feeding.

The compounds of formula I and their acid addition salt produce a decrease of blood pressure and of hypertension in warm-blooded animals, mammals, e.g., rats, dogs (when infused), monkeys, etc., and also birds.

The blood pressure decrease has been principally evaluated in rats.

Female rats (two or four) of about 300 g. weight are prepared for measuring blood pressure directly from the aorta through a chronic indwelling cannula [Weeks et al., Proc. Soc., Exptl, Biol. Med. Vol. 104, page 646 (1960)]. The mean arterial pressure is measured prior to, and 4 and 24 hours after drug administration. The administration in rats was oral, unit dosages of 50 mg./kg. or submultiples thereof. Compounds which reduce the mean arterial pressure by 10 or more mm of Hg are considered active compounds.

Results: (Blood pressure reductions in the rat) Compound Dosage Mean Blood Pressure mgJkg. in mm Hg Hour initial B. P.

0 +4 +24 2-acetamido 50 139 96 (43 I28 (1 l) 5,6-di- 25 I29 99 (30) I23 (6) methylbenzi- 12.5 135 I04 (31 137 (+2) midazole hy- 6.25 136 I25 (I 1) I34 (2) drochloride Z-acetamido- S0 138 109 129 G-mcthoxy 25 134 I 15 135 benzimidazole 2-propiona- 50 I34 I I0 126 mido-5,6-di- 25 131 116 128 methylbenzimidazole 2-acetamido- 50 I34 120 I 33 4-methylben- 25 I39 I28 I39 zimidazole Z-acetamido- 50 124 l 30 -trifluoro- 25 I35 I26 129 methylbenzimidazole Z-acetami- 50 I30 92 1 l2 do-5,6di- 25 I32 96 I28 methoxyben- 12.5 107 137 zimidazole 6.25 137 I15 I34 3 l 2 l 38 I22 I 33 The acute LD of Z-acetam ido-S ,6-

dimethylbenzimidazolo hydrochloride (U-27,518A); measured in rats, orally 359 mg./kg.

A 14-day duration study in dogs showed that 100 mg./kg. of U-27,518A was well tolerated. Even 300 mg./kg. for 4 days in dogs caused no letal effect.

The amount of compound of formula I and the pharmacologically acceptable salts thereof to be administered varies with weight, age, condition, route of administration and species of animal. In general a dose of 5 to 50 mg. daily per kg. in single or divided dosages is administered. The adult human daily dosage is preferably between I00-1,500 mg. in single or divided dosages.

The compound can also be administered with other active agents, e.g., with hypertensive agents, such as hydralazine hydrochloride, hexamethonium bromide, mecamylamine hydrochloride, phenoxybenzamine hydrochloride, guanethidine sulfate, methyldopa or the like; or with diuretic agents such as ethoxyzolamide, hydrochlorothiazide, trichloromethazide, acetazolamide; or with sedatives and tranquilizers, e.g., phenobarbital, pentobarbital, chloral hydrate, chlorpromazine, thioridazine, diazepam, chlordiazepoxide and the like.

In combination besides the benzimidazole, the following other active compounds can be administered with dosages as indicated: anti-anxiety and tranquilizing agents: chlorpromazine (5-50 mg.), meprobamate (100-400 mg.), ectylurea (100-300 mg.), chlordiazepoxide (5-50 mg.) and diazepam (2-15 mg.); antidepressants such as amitriplyline I-ICI 10-50 mg.), methylphenidate I-ICI (5-20 mg.), d-amphetamine SO (2-15 mg.) and methamphetamine I-ICI (2-15 mg.), antihypertensive and diuretic agents such as hydrochlorothiazide (15-50 mg.), hydralazine (IO-100 mg.), methyldopa (100-250 mg.), guanethidine (IO-50 mg.), ethoxzolamide (50-150 mg.) and reserpine (0.25-] mg. barbiturates such as phenobarbital (8-60 mg.) butabarital (8-60 mg.) and amobarbital (16-120 tion, but are not to be construed as limiting the scope thereof.

' EXAMPLE 1 2-Acetamido-5,6-dimethylbenzimidazole and its hydrochloride The 2-amino-5,6-dimethy1benzimidazole lref, L. Jo-

seph, J. Med. Chem., Vol 6, page 601 (1963)] was heated with acetic anhydride for 1 hour on the steam bath. The mixture was then poured into ice-water. A solid separated which was recovered by filtration, washed with water and dired to give 2-acetamido-5,6- dimethylbenzimidazole which after recrystallization from ethanol had a melting point of 306-307 C. Anal, calcd. for C fl N O:

C, 65.00 H, 6.45; N, 20.68.

Found: C, 65.11; H, 6.65; N, 20.38.

The hydrochloride of 2-acetamido-5,6- dimethylbenzimidazole was prepared by suspending 16.4 g. of the free base in methanol and adding an excess of alcoholic hydrogen chloride. The mixture was heated to boiling, filtered and the filtrate diluted with ether giving (two crops) 9.85 g. of 2-acetamido-5,6- dimethylbenzimidazole hydrochloride: The analytical purified sample had a melting point of 249296 C. Anal. calcd. for C l-l N o'l-lClz C, 55.11; H, 5.89; N, 17.53; C1, 14.79.

Found: C, 54.81; H, 5.61; N, 17.25; Cl, 15.13.

EXAMPLE 2 (alternate SCH; O

To asolution of 13.5 g. (0.10 mole) of 4,5-dimethylo-phenylenediamine in 250 ml. of CH OH was added 26 g. (0.10 mole) 1-acetyl-2-methyl-2-thiopseudourea hydriodide and the mixture heated on the steam-bath at reflux for 5-20 minutes. During this time, the product precipitated as a light brown solid. The solid was filtered and dried to give 14.25 g. (70 percent) of 2- acetamido-S,fi-dimethylbenzimidazole of melting point 306.5-307 C.

1n the manner given in Examples 1 or 2 the following other benzimidazoles were made: Z-acetamidobenzoimidazole (m. p. 323-326 C.). Z-acetamido-Smethylbenzimidazole (m. p. 294296 C.). 2-acetamido-4-methylbenzimidazole (m. p. 205208 C.). 2-acetamido-4,6-dimethylbenzimidazole 238-239 C.). 2-propionamido-5,6-dimethylbenzimidazole 288290 C.). 2-acetamido-4-methoxy-5methylbenzimidazole, m. p. 199-200 C.). 2-acetamido-5,-dimethoxybenzimidazole 316-318 C.). Z-acetamido-G-trifluoromethylbenzimidazole (m. p. 302-303 C. dec.). 2-acetamido-5methoxybenzimidazole l8l-l82 C.); 2-acetamido-6-chlorobenzimidazole (m. p. 31031 1 2-acetamido-5,6-dichlorobenzimidazole; 2-acetamido-4,-dibromobenzimidazole; 2-acetamido-S-iodobenzimidazole; Z-acetamido-5-fluoro-6 butoxybenzimidazole; 2-acetamido-4-hexoxybenzimidazole; 2-acetamido-4-hexylbenzimidazole; Z-acetamido-5pentylbenzimidazole; 2-acetamido-6-fluorobenzimidazole; and the like.

EXAMPLE 3 One thousand tablets for oral use, each containing mg. of 2-acetamidp-5,6-dimethylbenzimidazole hydrochloride, are prepared from the following ingredietns:

2-acetamido-5,6-dimethylbenzimidazole hydrochloride l00Gm.

Methylcellulose, U. S. P. (15 cps.) 6.5 Gm.

Talc 30Gm.

Calcium stearate 3.5 Gm.

The 2-acetamido-5,G-dimethylbenzimidazole hydrochloride and dicalcium phosphate are mixed well, granulated with 7.5 percent w/v aqueous solution of methylcellulose, passed through No. 8 screen and dried carefully. The dried granules are passed through a No. 12 screen, mixed with the talc and stearate and compressed into tablets.

The foregoing tablets are useful in the treatment of anxiety, hypertension and high blood pressure in adult humans ata dosage of two to 12 tablets per day.

EXAMPLE 4 The foregoing capsules are useful in treatment of adults with hypertension at a dosage of one to two capsules three times a day.

EXAMPLE An aqueous oral preparation containing in each 5 ml. 50 mg. of 2-acetamido-6-(trifluoromethyl)benzimidazole hydrochloride, is prepared from the following ingredients:

2-acetamido-6-(trifluoromethyl)benzimidazole drochloride 100 Gm.

Methylparaben 7.5 Gm.

Propylparaben 2.5 Gm.

Saccharin sodium 12.5 Gm.

Sucrose 12.5 Gm.

Glycerin 3,000 ml.

Tragacanth powder 100 Gm.

Orange oil flavor Gm.

F. D. and C. Orange dye 7.5 Gm.

Deionized water g. 5. 10,000 ml.

The foregoing composition is useful in the control of hypertension, high blood pressure, and hyperactive behavior problems in children at a dosage of one teaspoonful one to four per day.

EXAMPLE 6 A sterile aqueous suspension for intramuscular injection, containing in each ml. 100 mg. of 2-acetamido- 5,6-dimethylbenzimidazole hydrochloride is prepared from the following ingredietns:

2-acetamido-5,-dimethylbenzimidazole hydrochloride 100 Gm. Sodium carboxymethylcellulose, low viscosity l0 Polysorbate 80, U. S. P. 4 Gm. Propylparaben,-U. S. P. 0.4 Gm. Water for injection g. s. 1,000 ml.

The foregoing parenteral suspension is useful in the treatment of acute high blood pressure and agitation in a senile adult at a dosage of 1 ml. twice a day.

EXAMPLE} 7 EXAMPLE 8 One thousand m1. of an elixir, containing 100 mg. of 2-acetamido-5,6-diethylbenzimidazole hydrochloride and 8.1 mg. of phenobarbital in each 5 ml., is prepared from the following types of amounts of ingredients:

16.2 Gm. 1.0 Gm.

2-acetamido-5,6-diethylbenzimidazole ride 20 Gm.

Phenobarbital 1.62 Gm.

Citric acid 0.1 Gm.

F. D. C. Red No. 1

Saccharin 0.1 Gm.

Sucrose 200 Gm.

Oil of Spearmint 0.1 Gm.

Oil of Wintergreen 0.1 Gm.

Polysorbate U. S. P. l Gm.

Ethanol 200 ml.

Glycerin ml.

Water g. s. 1,000 ml.

The sugar is dissolved in 450 ml. of water and the citric acid, color and the 2-acetamido-5,6- diethylbenzimidazole hydrochloride added thereto. The phenobarbital and saccharin are added to the mixture of alcohol and glycerin and stirred until dissolved. The flavors are mixed with the polysorbate 80 and added to the alcohol-glycerin solution followed by the addition of the sugar solution and sufficient water to make 1,000 ml.

The syrup is useful in the treatment of hypertension of children at a dose of one teaspoonful three times 'a day.

hydrochlo- EXAMPLE 9 One thousand capsules for oral administration are prepared from the following ingredients:

2-butylamido-4-bromobenzimidazole citrate Lactose, anhydrous 132.5 Gm.

Magnesium stearate powder 2.5 Gm.

The powders are mixed thoroughly and filled into No. 3 gelatin capsules.

The capsules are useful in the treatment of high blood pressure of adults at a dose of one capsule four times a day.

EXAMPLE 10 One thousand capsules for oral administration are prepared from the following ingredients:

2-acetamido-4,5-dimethoxybenzimidazole chloride 50 Gm.

Lactose, anhydrous 207.5 Gm.

Magnesium stearate powder 2.5 Gm.

The powders are mixed thoroughly and filled into No. 3 hard gelatin capsules.

The capsules are useful in the treatment of hypertensive children at a dose of one capsule three times a day.

hydro- Following the procedure of the prior Examples 3.

wherein R is selected from the group consisting of hydrogen, alkyl of one to six carbom atoms, inclusive; alkoxy of one to six carbon atoms, inclusive, chlorine, bromine,'fluorine, and --CF;,, wherein R, is selected from the group consisting of hydrogen, alkyl of one to six carbon atoms, inclusive, chlorine, bromine, fluorine, alkoxy, of one to six carbon atoms, inclusive, and CF;,; and wherein R is alkyl of one to four carbon atoms, inclusive, or a pharmaceutical acceptably acid addition salt thereof, in association with a pharmaceutical carrier.

2. The method of claim 1, wherein the dosage to be administrated is from 50-1 ,500 mg. per day per human patient.

3. The method of claim 1 wherein the amount to be administered as single dose in animals is 5-50 mgJkg.

4. The method of claim 1 wherein the compound to be administered is 2-acetamido-5 ,6- dimethylbenzimidazole or a pharmacologically acceptable acid addition salt thereof. 

2. The method of claim 1, wherein the dosage to be administrated is from 50-1,500 mg. per day per human patient.
 3. The method of claim 1 wherein the amount to be administered as single dose in animals is 5-50 mg./kg.
 4. The method of claim 1 wherein the compound to be administered is 2-acetamido-5,6-dimethylbenzimidazole or a pharmacologically acceptable acid addition salt thereof. 